The recent introduction of highly active antiretroviral therapy (HAART) has dramatically altered the natural history of the AIDS epidemic. Nonetheless, the spectrum and extent of neurological injury in this setting, its relationship to neurocognitive function and responsiveness to changes in antiretroviral therapy remain important and unresolved issues. This application to renew support for the HIV MRS consortium proposes a five year cross sectional and longitudinal study to examine the pattern and dynamics of regional injury in the HIV infected brain in the setting of HAART. During the first two years of the current grant cycle, the MRS consortium identified significant relation- ships between metabolic abnormalities in the subcortical regions and cognitive function. Specifically, lower levels of NAA in the frontal white matter distinguished ADC from NA subjects; significant increases in Cho and MI were found in the neuroasymptomatic (NA) group compared to controls and neuropsychological performance was significantly correlated with metabolite levels in the subcortical regions, particularly the basal ganglia. MRS thus provides a valuable, noninvasive in vivo method to study and monitor changes in the cerebral microenvironment. Recent data support the hypothesis that cognitive impairment and its response to treatment correlates strongly with virological and immunologic activity in the CSF. Yet little is known about the relationships of these events to varying patterns of brain injury in the setting of HAART. The MRS consortium will undertake the following specific aims: 1) Examine the response of the cerebral microenvironment to varying levels of HIV RNA and chemokines in the CSF and peripheral compartments of 80 ADC and 80 NA subjects in relationship to changes in antiretroviral therapies and neurocognitive performance; 2) Determine the extent and significance of CNS injury in NA subjects with advanced disease in relationship to the development of neurocognitive impairment; and 3) Assess the evolution of brain injury patterns in ADC and NA subjects and the impact of host and viral factors using longitudinal statistical models. MRS studies of the basal ganglia, frontal white matter and cortex will be combined with measurements of cognitive function and assays of HIV RNA and markers of immune activation, including chemokines in the CSF and peripheral compartments of 100 subjects with HIV RNA greater than 2000 copies/ml undergoing changes in antiretroviral therapy and 60 subjects on stable therapy with undetectable plasma HIV RNA. Longitudinal and cross sectional analysis will be done incorporating various univariate, multivariate, and regression models that will allow us 1) to compare and correlate the magnitude and duration of the metabolic and neurocognitive response in relation to levels of HIV RNA and immune activation in the CSF and peripheral compartments and 2) to assess the relative contributions and interactions of these host and viral factors to brain injury and cognitive performance.